title: An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors.
abstract: Helicobacter pylori neutrophil-activating protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate antitumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Δ24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and MIP2-α in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours postvirus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting antitumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Ramachandran
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.forename: Alkwin
authors.initials: A
authors.lastname: Wanders
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
authors.forename: Fredrik
authors.initials: F
authors.lastname: Eriksson
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018358:Neuroendocrine Tumors / Q000276:immunology / Q000628:therapy*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000378:metabolism; D011995:Recombination, Genetic; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D037521:Virulence Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D037521:Virulence Factors; C092412:neutrophil-activating protein A, Helicobacter pylori